Recent investigations have shown that injured neurons express a programme, presumably involving the sequential switching of genes, that may control regrowth and axonal regeneration or induces cell death. The precise mechanisms and roles of such gene switching are poorly understood. Preliminary data from the PI's laboratory have demonstrated that spinal motoneurons in adult rat underwent a series of gene expression changes following axonal injuries. Some of these gene expressions seem to be related to regenerative processes, others seem to be associated with neuronal death. Peripheral nerve implantation seems to alter some gene expressions and reduce the death of motoneurons due to axonal injuries. The long-term goal of the proposed project is to study the mechanism underlying neuronal degeneration and regeneration, and to find new approaches which could prevent degeneration, promote regeneration, and improve functional recovery after neuronal injury. Four specific aims are included in the present proposal. (1). To examine gene expression changes in spinal motoneurons in response to axonal injuries in adult animals. Emphases will be focused on immediate early genes, neurotrophin receptor genes, growth associated genes, and nitric oxide synthase. (2). To investigate whether gene expression changes are associated with neuronal degeneration or regeneration. If so, to determine which is related to degeneration and which is related to regeneration. (3). To test the effect of a microsurgical procedure, the peripheral nerve system (PNS) graft implantation, on motoneuron survival and regeneration following axonal injury, and to determine which gene expression is associated with the survival and regeneration of injured motoneurons. (4). To investigate whether neurotrophic factors could prevent motoneuron death and promote regeneration following axonal injury. If so, to determine whether such effect is achieved by modifying certain gene expressions in injured motoneurons. In the proposed experiments, adult motoneurons will be used as experimental model. Advantage of this model is that neuronal death or regeneration in spinal motoneurons can be reliably manipulated by experimental procedures. In the proposed experiments, gene expression changes in spinal motoneurons will be studied under three different injury conditions which include: 1). distal spinal root axotomy (which does not cause motoneuron death), 2). spinal root avulsion (which causes a significant motoneuron death), and 3). root avulsion followed by PNS graft implantation or/and neurotrophic factor treatments (which prevents injured motoneurons from death and allows them to regenerate). These experimental procedures allow us to examine gene expressions and their modifications in different cases of motoneurons after axonal injuries. Gene expressions will be examined using immunocytochemistry and in situ hybridization techniques. Cell death will be assessed by neuronal counts following the experimental manipulations. Axonal regeneration will be assessed by a double fluorescent retrograde labeling technique: Data obtained from these experiments should provide a better understanding of events leading to neuronal death and plasticity and may lead to therapeutic interventions that prevent neuronal death and enhance regeneration.